The tripeptide hormone fragment Pro--L--Leu--Gly--NH.sub.2, known as melanotrophic release-inhibiting hormone or MIF, has been reported as having pronounced effects on the central nervous system. For example MIF has been found to potentiate the behavioral effects of L-DOPA and apomorphine, attenuate puromycin-induced amnesia, and facilitate morphine dependence, thus suggesting that MIF should have activity against Parkinson's disease as well as have a "mood-elevating" effect. See Ehrensing et al, "Clinical Investigations for Emotional Effects of Neuropeptide Hormones," Pharmacol. Biochem. Behav., 5 (Suppl. 1), 89 (1976). Both of these actions have been supported by animal tests and clinical data. (For Parkinsonism, see Barbeau et al, "Double-blind Evaluation of Oral L-Prolyl-L-leucyl-glycine Amide in Parkinson's Disease," Can. Med. J., 114, 120 (1976), and for depression see Ehrensing et al, "Dose-Related Biphasic Effect of Prolyl-Leucyl Glycinamide (MIF-I) in Depression," Am. J. Psychiatry, 135, 562 (1978).) Practical use of MIF has been hindered, however, because MIF is rapidly cleaved by enzymatic action, and thus its half-life is very short. As a consequence, to enable significant effects to be obtained over a useful time period, it is necessary to administer large doses of MIF by intravenous infusion over long periods of time.
Because of this difficulty, attempts have been made to synthesize MIF analogs which will possess the same pharmacologic activity as MIF, but will be less susceptible to inactivation by enzymatic cleavage. For example, Voith, in "Synthetic MIF Analogues Part II: Dopa Potentiation and Fluphenazine Antagonism," Arzneimittel-Forsch., 27, 2290 (1977), reports efforts to improve effective MIF life by introducing a methyl substituent on the amino group of the central leucine (Leu) peptide, the use of the N-methyl-D-Leu stereoisomeric peptide, and the replacement of the 3-glycine (Gly) residue with D-alanine (D-Ala). However, such compounds were reported to have low potencies as compared with the parent MIF.
Another effort, reported by Bjorkman et al in "Tripeptide Analogues of Melanocyte-Stimulating Hormone Release-Inhibiting Hormone (Pro--Leu--Gly--NH.sub.2) as Inhibitors of Oxotremorine-Induced Tremor", J. Med. Chem., 22, 931 (1979), involved replacement of the proline residue (Pro) by the pyroglutamic acid residue (pGlu), and the alkylation of the terminal amide group of the Gly--NH.sub.2 residue. The reported data indicate that the activities of the resulting analogs against oxotremorine-induced tremor ranged from nil to significant increases in potency as compared to the parent MIF. No data were presented with respect to half-life of these agents. Furthermore, since these compounds were injected i.p., and thus may have been severely degraded through enzymatic degradation in the liver before reaching the brain, the post-hepatic dosage of these materials, and thus their true activity, is presently unknown.